A multicenter prospective cohort study comparing random biopsies with Wide-Area Transepithelial brush-Sampling (WATS) for surveillance of Barrett*s esophagus.;The WATS-EURO2 study

Esophageal adenocarcinoma (EAC) is a disease with a poor prognosis at advanced
stages. Identifying esophageal adenocarcinoma at an early stage allows for
endoscopic treatment to reduce mortality and morbidity for these treated
patients. Adequate surveillance strategies with appropriate risk stratification
are therefore essential.

The current endoscopic surveillance protocol relies on systemic four-quadrant
biopsy at 2-cm intervals of the BE segment, with additional targeted biopsies
from visible abnormalities. Obtaining random biopsies is time consuming, and it
results at best in sampling less than 5% of the BE surface area (2). Thus,
significant sampling error is inevitable. Sampling the BE segment with a brush
has the theoretical advantage of larger field sampling and might therefore
increase the detection of dysplasia. =

In the European WATS study (*Euro-WATS1*) the WATS-system was compared with
random biopsies in a cohort of patients referred with low-grade dysplasia
(LGD), high-grade dysplasia (HGD) or early cancer after removal of all visible
abnormalities. Eligible cases underwent random biopsies and WATS brushings
after randomizing the order of sampling. The study showed no significant
differences in the detection rate for HGD or EAC between random biopsies and
WATS brushings. The brush detected 39/48 HGD/EAC cases versus 30/48 for random
biopsies (p=0.12). The value of the WATS-3D brush as an adjunct to random
forceps biopsies however, was 48/147 vs 30/147; difference 12%, with a number
needed to treat of 8. Moreover, the brush had a significantly shorter procedure
time than random biopsies with a larger difference in longer BE segments.
Another strength of the WATS brush, compared to random biopsies, is that it
paves the way towards a preferred (future) trans-oral sampling instead of
endoscopic sampling. Key element in the adjunctive value of WATS is the
clinical relevance of *WATS-positive-biopsy-negative*. One may argue that the
morphological changes of dysplasia-positive WATS samples clearly correspond to
those defining dysplasia in biopsy samples and therefore are merely different
representations of the same disease which is now diagnosed at an earlier stage.
Others argue that the WATS-system, by being more sensitive to detect dysplasia,
simply dilutes the disease reservoir with clinically less severe cases which do
not warrant the same therapeutic approach as in cases with a biopsy based
diagnosis of dysplasia. The natural history of *WATS-positive-biopsy-negative*
cases can, however, not be investigated in the EURO-WATS1 study because this
was a transversal study with no subsequent follow-up and with the vast majority
of cases having undergone ablation therapy based on their referral diagnosis
and/or outcome of the endoscopic resection of visible lesions. Another
limitation of the EURO-WATS1 study was the relatively high rate of WATS
brushings that were deemed ineligible for assessment of the smears. In the
study 23/172 (13%) of cases had suboptimal WATS samples, despite the fact that
the corresponding cellblocks showed adequate cellularity.
A second European WATS study (*WATS EURO 2 study*) will be performed in which,
after the baseline endoscopy with WATS brushing and random biopsies, endoscopic
follow-up is continued until a biopsy-based diagnosis of HGD or cancer is made.
The WATS EURO 2 study will therefore allow us to study the natural history of
WATS-positive-biopsy-negative cases, will enable us to re-evaluate the role of
the WATS-3D brush as a potential substitute for random sampling, after
optimizing sample collection and preparation in the study. Finally, the samples
collected in this study will also allow us to perform future biomarker studies
on both the brush and biopsy material, to find the best sampling method for
biomarker risk stratification in the future.

We aim to study the rate of developing a biopsy-based diagnosis of high-grade
dysplasia (HGD) and EAC in BE patients in a prospective cohort of 204 BE
patients at high risk of progression (i.e. after endoscopic removal of visible
lesions containing HGD/EAC and/or a diagnosis of low-grade dysplasia (LGD)) as
well as in 204 BE patients with a non-dysplastic BE (NDBE) undergoing standard
BE surveillance. In these patients we will combine biopsy sampling with WATS at
baseline and all follow-up endoscopies during a 3-year follow-up period. This
will allow us to study the natural history of
WATS-positive-biopsy-negative-cases and of WATS-specific outcomes such as
basal-crypt dysplasia. The study also allows us to collect specimens for future
biomarker studies that may help to predict progression to HGD/EAC in the
absence of morphological features of dysplasia.

This is an international multicentre, prospective study in 11 European medical
centres with a tertiary referral function for endoscopic detection and
treatment of early Barrett*s neoplasia.

Our study population consists of patients with either a flat Barrett's
esophagus (BE) with low grade dysplasia (LGD) or high grade dysplasia (HGD) or
a flat BE after removal of visible lesions with LGD, HGD or early carcinoma. At
baseline, an imaging endoscopy will be performed and after confirmation of
absence of visible lesions, WATS brushing of the Barrett*s segment will be
performed followed by random 4 quadrant mucosal biopsies every 2 cm. If the
biopsies subsequently show HGD or esophagus adenocarcinoma (EAC), the patient
has reached the study endpoint and will be managed according to the
institution*s standard of care. If the baseline biopsies show LGD, indefinite
(IND) or non dysplastic BE, patient will not undergo ablation therapy and will
be scheduled for endoscopic follow-up. In case of prior endoscopic resection
for a visible lesion containing HGD/EAC the follow-up schedule consists of
endoscopies at 3, 6, 9, 12, 18, 24 and 36 months. For patients with a referral
diagnosis of LGD, the follow-up consists of endoscopies at 6 and 12 months and
annually thereafter


It is undisputed that patients referred with LGD, HGD or early cancer should
have all visible lesions removed by ER techniques. In general, the endoscopic
resection specimen will then show a diagnosis of HGD or early cancer. Follow-up
studies have shown that the chance of the development of metachronous HGD/EAC
in the remaining BE segment is about 10% per year. Therefore ablation therapy
is advised for the remaining BE segment. The same 10% annual progression rate
to HGD/EAC applies for patients with a confirmed diagnosis of LGD. For this
category guidelines suggest that ablation therapy may be indicated for cases in
which this diagnosis, apart from being confirmed by an expert pathologist, is
also reproduced in subsequent endoscopies. The actual decision to ablate the
remaining segment after endoscopic resection of HGD/EAC or to prophylactically
ablate for LGD, is made on a per patient basis in which age and comorbidity are
important factors to regard. Follow-up studies after ER of visible lesions
containing HGD/EAC have found that metachronous lesions are found to be
endoscopically treatable with the majority of patients not developing recurrent
disease. The same holds for prophylactic ablation in cases with LGD: a
significant proportion of patients will not progress or not even manifest their
baseline diagnosis of LGD upon follow-up. In the SURF-study, 30% of the
LGD-patients randomized to endoscopic surveillance did not have their LGD
diagnosis reproduced during 4 subsequent endoscopies in 3-years follow-up and
all cases that progressed to HGD/EAC were diagnosed at an endoscopically
curable stage.
Furthermore, RFA still is accompanied by complications such as esophageal
stenosis and requires multiple hospital visits. Even upon complete endoscopic
eradication of all Barrett*s mucosa, guidelines still dictate endoscopic
surveillance after ablation virtually at the same frequency as for Barrett*s
cases that are not prophylactically treated.
Therefore, keeping Barrett*s patients under strict endoscopic surveillance
after ER of visible lesions or for flat LGD is a very acceptable treatment
strategy that does not divert from current guidelines.